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Clinical Trial
. 2014 Nov 20;32(33):3753-61.
doi: 10.1200/JCO.2013.54.5384. Epub 2014 Oct 20.

Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer

José Baselga  1 , Javier Cortés  2 , Seock-Ah Im  2 , Emma Clark  2 , Graham Ross  2 , Astrid Kiermaier  2 , Sandra M Swain  2
Affiliations
Clinical Trial

Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer

José Baselga et al. J Clin Oncol. .

Abstract

Purpose: To explore the prognostic and/or predictive value of human epidermal growth factor receptor 2 (HER2) pathway-related biomarkers in the phase III CLEOPATRA study of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel as first-line treatment for patients with HER2-positive metastatic breast cancer.

Patients and methods: Mandatory tumor and serum samples were collected (N = 808; 58% to 99.8% were assessable), and amphiregulin, betacellulin, epidermal growth factor (EGF), transforming growth factor alpha, EGF receptor, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FCγR were assessed using appropriate assays. Two types of correlations were investigated using univariable Cox regression: predictive effects (qualitative association of biomarkers with pertuzumab progression-free survival [PFS] benefit) and prognostic effects independent of treatment arm (relationship of each biomarker to clinical outcome in both arms pooled).

Results: Pertuzumab consistently showed a PFS benefit, independent of biomarker subgroups (hazard ratio < 1.0), including estrogen receptor-negative and -positive subgroups. High HER2 protein, high HER2 and HER3 mRNA levels, wild-type PIK3CA, and low sHER2 showed a significantly better prognosis (P < .05). PIK3CA showed the greatest prognostic effect, with longer median PFS for patients whose tumors expressed wild-type versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months).

Conclusion: Through comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors.

Trial registration: ClinicalTrials.gov NCT00567190.

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